PHYLOGENOMIC, TRANSCRIPTOMIC, VIROMIC, AND IMMUNOPROTEOMIC DETERMINANTS OF NECROTIZING ENTEROCOLITIS

坏死性小肠结肠炎的系统基因组、转录组、病毒组和免疫蛋白质组决定因素

• 批准号: 10164835
• 负责人: Gautam Dantas
• 金额: $ 58.45万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-06 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10164835
• 关键词: Anaerobic Bacteria; Appearance; Archives; Bacteria; Bacteriophages; Biological; Biological Markers; Biology; Birth; Case Fatality Rates; Child; Cities; Clinical; Collection; Complication; Consent; Consequentialism; Data; Development; Enrollment; Event; Feces; Functional disorder; Gammaproteobacteria; Genetic Transcription; Genomics; Genotype; Gestational Age; Goals; Human; Immune response; Individual; Infant; Inflammation; Injury; Intervention; Intestines; Knowledge; Lead; Learning; Life; Link; Low Birth Weight Infant; Metadata; Microbe; Modeling; Molds; Morbidity - disease rate; Necrotizing Enterocolitis; Neonatal Intensive Care Units; Oklahoma; Organism; Outcome; Personal Satisfaction; Phylogenetic Analysis; Plasma; Play; Population; Premature Birth; Premature Infant; Prevention strategy; Process; Prospective cohort study; Publications; Publishing; Reaction; Resources; Risk; Role; Sampling; Series; Serum; Severities; Site; Specimen; System; Testing; Time; Transcriptional Activation; Very Low Birth Weight Infant; Virus; Work; bacterial community; base; case control; cohort; congenital heart disorder; dysbiosis; experience; gut bacteria; insight; intestinal injury; metabolomics; microbial; microbial host; microbiome; microbiota; mortality; novel; organ injury; prevent; stool sample; transcriptomics

Project Summary Necrotizing enterocolitis in very low birth weight infants remains a major challenge. Our reactive clinical approach to necrotizing enterocolitis has changed little in four decades. Morbidity and mortality from necrotizing enterocolitis remain unacceptably high, and preventive strategies rely on interventions with limited, if any, efficacy. We have assembled an extensive set of specimens, accompanied by rich clinical metadata, with which to define mechanisms that underlie the development of necrotizing enterocolitis in very preterm infants. Our proposal extends our recently published findings that a gut bacterial dysbiosis, characterized by over-representation of Gammaproteobacteria and under-representation of obligate anaerobic bacteria, precede, and plausibly contribute to, the development of necrotizing enterocolitis. Our overarching hypothesis is that identifiable microbial and/or host mechanisms signify an infant at risk for necrotizing enterocolitis. Our long-term goals are to use our knowledge of microbial-driven pathophysiology in necrotizing enterocolitis to build interventions to prevent the assembly of dysbiotic gut bacterial populations, to characterize the host biology prior to the sudden appearance of necrotizing enterocolitis. By generating these data, we hope to lessen the severity of necrotizing enterocolitis, or to prevent it altogether. Our Specific Aims are: (1) Conduct a comprehensive genomic analysis of gut bacteria prior to necrotizing enterocolitis onset, and (2) Define the gut biology and host response prior to necrotizing enterocolitis onset. All specimens from cases will be those obtained before this event occurred. Control materials will be matched to cases, according to gestational age at birth, and day of life specimens were produced. To accomplish these Aims, we will use our archive of pre-event stools and sera/plasmas from 977 very low birthweight infants from three neonatal intensive care units. Forty-six of these infants experienced NEC, after excluding those who also had congenital heart disease. We will employ genomic characterization of isolates, transcriptomics, metabolomics, viromics, and immunoproteomics in coordinated analyses to illuminate microbial and host biology underlying necrotizing enterocolitis. We will also interrogate populations of bacteria associated with protection from necrotizing enterocolitis. All studies will initially analyze a primary cohort from St. Louis, and then validate findings in specimens from Oklahoma City and Louisville. These case-control and time-series comparisons will provide mechanistic insight into an intractable and highly consequential complication of preterm birth, using an exceptionally relevant system, i.e., the colonized human infant. By project conclusion, we will generate mechanistically-informed data to guide attempts to better anticipate, treat, or, ideally, prevent, necrotizing enterocolitis, a devastating complication of preterm birth.

项目概要 极低出生体重婴儿的坏死性小肠结肠炎仍然是一个重大挑战。我们的反应性临床 四十年来，治疗坏死性小肠结肠炎的方法几乎没有变化。发病率和死亡率来自 坏死性小肠结肠炎的发病率仍然高得令人无法接受，预防策略依赖于有限的干预措施， 如果有的话，功效。我们收集了大量样本，并附有丰富的临床元数据， 以此来定义极早产儿坏死性小肠结肠炎发生的机制 婴儿。我们的建议扩展了我们最近发表的研究结果，即肠道细菌失调，其特征是 γ-变形菌门的过度代表性和专性厌氧细菌的代表性不足， 发生在坏死性小肠结肠炎之前，并且可能促成坏死性小肠结肠炎的发生。 我们的首要假设是，可识别的微生物和/或宿主机制表明婴儿处于 坏死性小肠结肠炎的风险。我们的长期目标是利用我们的微生物驱动知识 坏死性小肠结肠炎的病理生理学，以制定干预措施，防止肠道菌群失调 细菌种群，以在突然出现坏死之前表征宿主生物学 小肠结肠炎。通过生成这些数据，我们希望减轻坏死性小肠结肠炎的严重程度，或预防 完全是这样。 我们的具体目标是：(1) 在使用之前对肠道细菌进行全面的基因组分析 坏死性小肠结肠炎发作，以及 (2) 确定坏死前的肠道生物学和宿主反应 小肠结肠炎发作。病例中的所有标本都将是该事件发生之前获得的标本。控制 根据出生时的胎龄和出生日期，将材料与病例进行匹配 产生的。 为了实现这些目标，我们将使用来自 977 名活动前粪便和血清/血浆的档案 来自三个新生儿重症监护病房的低出生体重婴儿。其中 46 名婴儿经历过 NEC， 在排除那些也患有先天性心脏病的人之后。我们将利用基因组表征 协调分析中的分离株、转录组学、代谢组学、病毒组学和免疫蛋白质组学以阐明 坏死性小肠结肠炎的微生物和宿主生物学。我们还将询问细菌种群 与预防坏死性小肠结肠炎有关。所有研究最初都将分析来自 圣路易斯，然后验证俄克拉荷马城和路易斯维尔标本中的发现。这些病例对照和 时间序列比较将为解决棘手且非常重要的问题提供机械见解 早产并发症，使用一个特别相关的系统，即殖民人类婴儿。 通过项目结束，我们将生成机械信息数据来指导更好的尝试 预测、治疗或最好预防坏死性小肠结肠炎，这是早产的一种破坏性并发症。

项目成果

Approaches for characterizing and tracking hospital-associated multidrug-resistant bacteria.

• DOI: 10.1007/s00018-020-03717-2
• 发表时间: 2021-03
• 期刊: Cellular and molecular life sciences : CMLS
• 作者: Blake KS;Choi J;Dantas G
• 通讯作者: Dantas G

Cotrimoxazole Prophylaxis Increases Resistance Gene Prevalence and α-Diversity but Decreases β-Diversity in the Gut Microbiome of Human Immunodeficiency Virus-Exposed, Uninfected Infants.

• DOI: 10.1093/cid/ciz1186
• 发表时间: 2020-12-31
• 期刊: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
• 作者: D'Souza AW;Moodley-Govender E;Berla B;Kelkar T;Wang B;Sun X;Daniels B;Coutsoudis A;Trehan I;Dantas G
• 通讯作者: Dantas G

The effect of legume supplementation on the gut microbiota in rural Malawian infants aged 6 to 12 months.

• DOI: 10.1093/ajcn/nqaa011
• 发表时间: 2020-02
• 期刊: The American journal of clinical nutrition
• 作者: M. I. Ordiz;Stefan Janssen;G. Humphrey;G. Ackermann;Kevin B. Stephenson;Sophia E. Agapova;O. Divala;Yankho Kaimila;K. Maleta;Caroline Zhong;R. Knight;Indi Trehan;P. Tarr;B. Rusconi;M. Manary

Effect of amoxicillin on the gut microbiome of children with severe acute malnutrition in Madarounfa, Niger: a retrospective metagenomic analysis of a placebo-controlled trial.

• DOI: 10.1016/s2666-5247(23)00213-6
• 发表时间: 2023-11
• 期刊: LANCET MICROBE
• 影响因子: 38.2
• 作者: Schwartz, Drew J.;Langdon, Amy;Sun, Xiaoqing;Langendorf, Celine;Berthe, Fatou;Grais, Rebecca F.;Trehan, Indi;Isanaka, Sheila;Dantas, Gautam
• 通讯作者: Dantas, Gautam

Draft Genome Sequence of a Mycobacterium Strain Isolated from a Clinical Wound Sample.

• DOI: 10.1128/mra.00170-22
• 发表时间: 2022-07-21
• 期刊: Microbiology resource announcements
• 影响因子: 0.8